Reduced action of insulin glargine on protein and lipid metabolism: possible relationship to cellular hormone metabolism

Insulin analogues are used in the treatment of diabetes to mimic physiological insulin secretion. Glargine is used to provide basal insulin levels. Previous work has shown no differences in glucose uptake when glargine was compared to native insulin. The action of insulin on protein and lipid metabolism is studied infrequently, but these important actions should be considered with insulin analogues. In HepG2 cells, protein degradation was inhibited significantly less by glargine (15% over 3 hours) than by insulin (approximately 20% over 3 hours) (P < .05). Lipid metabolism was investigated in 3T3-L1 cells. In these cells glucose oxidation to CO2 was effected equally, but glargine was less potent than insulin at inhibiting epinephrine-stimulated lipolysis (EC50 = 1.4 v 0.35 nmol/L, P < .001) and at stimulating lipogenesis (EC50 = 1.27 v 8.06 nmol/L, P < .01). Since the action of insulin on protein and lipid metabolism has been suggested to be due to the metabolism of the hormone, we compared the cellular handling of 125I[A14]-glargine to 125I[A14]-insulin in HepG2 cells. While binding of glargine to the insulin receptor was identical to insulin, degradation of glargine was reduced compared to insulin (16.3% +/- 0.3% v 21.6% +/- 0.4% degraded/h, P < .01). Less degraded glargine than insulin was released from cells previously loaded with radiolabeled material (50.1% +/- 2.4% v 58.3% +/- 1.4%/2 h, P < .02). The amount of intact glargine released was concomitantly increased compared to insulin (44.8% +/- 2.6% v 35.8% +/- 1.4%/2 h, P < .02). These data provide further evidence for a relationship between insulin metabolism and insulin action on protein and lipid metabolism; however, the clinical relevance of these differences is hard to realize, since for the most part glargine, used as a basal insulin, is administered in addition to other shorter-acting insulin or analogues, and their effects will mask or reduce glargine effects on lipolysis and protein degradation. However, these studies do show that properties of insulin other than glucose metabolism and mitogenesis must be considered when studying insulin analogues.